Elucidating rotaviral condensate structure and function for future antiviral targeting

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Nearly all known human viruses replicate within specialised compartments in cells called viroplasms. The phase-separating nature of these structures makes them promising antiviral targets in rotaviruses; combining high-throughputmicrofluidics approaches with biophysics and molecular virology will offer unique insights into their behaviour. For example, NSP5 associated with condensate formation phosphorylates throughout infection. Microfluidics would allowinvestigations into the effects of phosphorylation on phase boundaries; alongside in vivo studies, this could reveal why viroplasms solidify over time. The role of viroplasm-associated RNA in phase separation and particle assembly alsoremains unclear. While the disordered state of these molecules makes structure prediction challenging, reverse genetics can be used to rescue viruses and their RNA. By detecting differential FRET emissions inside droplets and comparingwith known structures, structural changes in viral RNA under various conditions could be identified. Additionally high-throughput screening can identify potential antivirals that specifically aggregate into and disrupt viral condensates. Abetter understanding of viral phase separation, along with the skillset I will have acquired from this project, could then be applied to other infectious systems. This is of particular importance when facing of a global crisis caused by antiviral and antimicrobial resistance.